Asthma, GERD and Laryngeal Pharyngeal Reflux (LPR)

(1)

Asthma, GERD and Laryngeal

Pharyngeal Reflux (LPR)

Richard F. Lockey, M.D.

Division of Allergy and Immunology

Department of Internal Medicine

University of South Florida

College of Medicine

and

James A. Haley Veterans’ Medical Center

Tampa, Florida

(2)

Outline

1.Definition and Description 2.Symptoms

3.Prevalence and Impact 4.Pathogenesis

5.Complications 6.Diagnosis

7.GERD and Upper Airway Disorders 8.GERD and Asthma

(3)

Outline

1.Definition and Description

2.Symptoms

(4)

Definitions

• GER: backflow of stomach contents into the esophagus, usually acidic

• GERD: abnormal GER

– DeMeester score with pH probe

– Dobhan criteria for proximal GERD

– May result in inflammation of esophagus • LPR: laryngopharyngeal reflux

(5)

Dent et al. Gut 1998

Definition of GERD –

Genval Workshop

• “The term GERD should be used to include all individuals who are exposed to the risk of

physical complications from gastroesophageal reflux, or who experience clinically significant impairment of health-related well-being (quality of life) due to reflux-related symptoms, after

adequate reassurance of the benign nature of their symptoms”

(6)

Heartburn

• Heartburn is the most common manifestation of GERD

• The word ‘heartburn’ is often misinterpreted by patients1

• Description of heartburn as “a burning feeling rising from the stomach or lower chest up towards the

neck” can help patients to recognize this symptom1 • When heartburn is the main or only symptom

experienced by a patient, it is strongly suggestive of the presence of GERD2

1_{Carlsson et al. Scand J Gastroenterol 1998} 2_{Klauser et al. Lancet 1990}

(7)

Typical symptoms of GERD other

than heartburn

• Regurgitation (GER) = an effortless return of gastric contents into the esophagus and

frequently into the mouth; often confused with vomiting

• Dysphagia = difficulty swallowing

(8)

Definition

• Laryngopharyngeal Reflux:

a form of

gastroesophageal reflux disease that

produces prominent symptoms and signs in

the pharynx and larynx characterized by

acute, chronic, and intermittent laryngitis

and pharyngitis.

http://www.medilexicon.com/medicaldictionary.php

(9)

Outline

1.Definition and Description

2.Symptoms

(10)

Atypical symptoms of GERD

• Chest pain • Hoarseness • Chronic cough • Sore throat • Wheezing • Throat clearing • Globus • Laryngospasm • Dental erosion

1_{Mujica et al. Postgrad Med 1999} 2_{DeVault et al. Am J Gastroenterol 1999}

(11)

Johnsson et al. Gullet 1992

Symptom patterns in GERD

• Reflux-related symptoms occur predominantly after meals

• Reflux-related symptoms are often triggered by

– unusually large meals

– fatty, spicy, or acidic foods

– bending, stooping, or lying down

– lifting, straining, or other strenuous activities

• The frequency of reflux-related symptoms varies widely

(12)

Distribution of GERD symptoms

over 24 hours

Johnsson et al. Gullet 1992

Time of day 0 15 30 45 6 am 9 am 12 n oon 3 pm 6 pm 9 pm 12 m idni ght 3 am 6 am N u m b e r o f e p is o d e s o f re fl u x s y m p to m s /h o u r (m e a n x 1 0 2 )

Breakfast Lunch Dinner

(13)

Outline

3.Prevalence and Impact

4.Pathogenesis 5.Complications 6.Diagnosis

(14)

Stanghellini. Scand J Gastroenterol 1999 8 10 14 17 22 10 4 10 11 18 0 5 10 15 20 25 Italy n = 999 Japan n = 500 Scandinavia n = 1010 Canada n = 1036 United States n = 1020 Heartburn Regurgitation 3 -m o n th p re v a le n c e ( % )

(15)

Age-adjusted prevalence of GERD symptoms:

the DIGEST study

Stanghellini. Scand J Gastroenterol 1999

Age in years 3 -m o n th p re v a le n c e ( % )

The proportion of respondents experiencing symptoms increased significantly with

age (P<0.001).

N=5581

Includes all respondents from US, Canada, European countries, and Japan.

0 5 10 15 20 <21 21-35 36-50 51-65 >65

(16)

24.4%

>1/ week

Oliveria et al. Arch Intern Med 1999 0 5 10 15 20 25 30 21.5% Daily 16.5% >1/month 11.5% 1/month 13.8% <1/month Frequency of heartburn % r e s p o n d e n ts

Frequency of heartburn

11.3% 1/week

(17)

0 10 20 30 40 50 60

No heartburn Mild heartburn Moderate heartburn Severe heartburn

P a ti e n ts w it h h e a rt b u rn ( % ) Grade A (n=1466) Grade B (n=1634) Grade C (n=869) Grade D (n=314)

Levine et al. Am J Gastroenterol 1999

Severity of GERD symptoms does not

correlate with severity of disease

(18)

Patients presenting

with reflux symptoms (n = 97)

46% 42% 12% Barrett’s esophagus No erosive esophagitis Erosive esophagitis

Winters et al. Gastroenterology 1987

Approximately half of all patients with

reflux symptoms have erosive

(19)

1_{Smout. Aliment Pharmacol Ther 1997} 2_{Lundell et al. Gut 1999}

Symptoms are not reliably predictive of

mucosal damage

• Patients with and without erosive esophagitis

are similar with respect to symptom severity1

• Patients with and without erosive esophagitis

are similar with respect to symptom frequency1

• Patients with different grades of erosive

esophagitis are similar with respect to symptom severity2

(20)

Outline

3.Prevalence and Impact

4.Pathogenesis

(21)

Pathogenesis of GERD –

overview

• GERD results from exposure of the esophageal mucosa to refluxed gastric contents

• In most patients with GERD, exposure of the esophagus to refluxate is greater than normal • In a minority of patients, exposure is within

normal limits; in these patients, GERD may be due to decreased mucosal resistance to

refluxate

1_{DeVault et al. Am J Gastroenterol 1999} 2_{Dent et al. Gut 1998}

(22)

• Ineffective peristalsis

• Reduced salivary secretion

• Reduced secretion from esophageal submucosal glands

(23)

• Inappropriate and prolonged transient relaxations • Reduction in basal LES pressure/tone

LES ‘dysfunction’

(24)

• May trap a reservoir of gastric contents above the diaphragm,

increasing reflux

• May compromise LES function

(25)

• Pregnancy • Obesity • Bending • Straining • Coughing • Tight clothes

(26)

• May result in an increase in the

volume of gastric contents available for reflux into the esophagus

• Exact role in GERD remains to be

clarified

(27)

Causes of increased exposure of the

esophagus to gastric refluxate

(28)

Medications that may aggravate GERD

symptoms by damaging the esophageal

mucosa

• Tetracycline • Quinidine

• Potassium chloride tablets • Iron salts

• Aspirin and other NSAIDs • Bisphosphonates

(29)

Medications that may aggravate GERD

symptoms by impairing LES function

• β-adrenergic agonists • Theophylline • Anticholinergics • Tricyclic antidepressants • Progesterone • α-adrenergic antagonists • Diazepam • Calcium channel blockers

(30)

Outline

5.Complications

6.Diagnosis

(31)

• Esophageal – Barrett’s esophagus – adenocarcinoma – stricture – ulceration – bleeding • Extra-esophageal – asthma – reflux laryngitis – vocal cord ulcers – subglottic stenosis – tracheal stenosis

Complications of GERD

(32)

Outline

5.Complications

6.Diagnosis

(33)

Diagnostic methods in GERD

• History • Rhinoscopy • Endoscopy • Empiric therapy • pH monitoring • Radiology

(34)

History

• History-taking is the primary diagnostic tool for GERD

• Typical GERD can usually be diagnosed on the basis of history alone

(35)

Outline

7.GERD and Upper Airway Disorders

8.GERD and Asthma 9.Management

(36)

GERD and Chronic Rhinosinusitis

•

• Upper respiratory symptoms frequent among Upper respiratory symptoms frequent among subjects with symptomatic GERD Dx

subjects with symptomatic GERD Dx’’d by d by esophageal study

esophageal study

•

• GERD associated with chronic rhinosinusitis GERD associated with chronic rhinosinusitis in children and adults

in children and adults

Theodoropoulos DS et al.

Theodoropoulos DS et al. Am J Resp Crit Care Med Am J Resp Crit Care Med 2001;164:722001;164:72--66 Barbero GJ.

Barbero GJ. Otolaryngol Clin North Am Otolaryngol Clin North Am 1996;29:271996;29:27--3838 Phipps CD et al.

Phipps CD et al. Arch Otolaryngol Head Neck SurgArch Otolaryngol Head Neck Surg 2000;126:8312000;126:831--66 Ulualp SO et al.

Ulualp SO et al. Am J RhinolAm J Rhinol 199;13:197199;13:197--202202 DiBaise et al.

(37)

GERD and Upper Airway Disorders

Factors Associated with GERD

• Lifestyle issues

– EtOH, cigarette smoking • Obesity

• Medications

– Beta agonists, theophylline, first generation antihistamines

• Food

(38)

GERD and Upper Airway Disorders

(39)

Pathophysiology

• Direct irritation by acid

• Neurogenic reflex (increased vagal tone) • Neurogenic inflammation

(40)

GERD and Upper Airway Disorders

(41)

Pathophysiology

(42)

Pathophysiology

Odds Ratio of GERD

URS Score > 4 1.5

URS Score = 8 3.8

URS Score = 11 6.8

(43)

Pathophysiology

Upper Airway Symptoms Related to GER or GERD

• Throat clearing • Cough

• Voice change • Post nasal drip

• Hoarseness • Nasal congestion

(44)

Upper Airway Symptoms Possibly Related to GER or GERD

•Rhinorrhea • Ear ache/fullness

•Sneezing • Otitis media with effusion

•Sinusitis • Serous otitis media

•Sinus Headache • Upper airway itching

GERD and Upper Airway Disorders

Pathophysiology

(45)

Pathophysiology

(46)

Normal Larynx with GERD

(47)

Belafsky Score for Diagnosis of LPR (0-4 score for each component)

7 or more is diagnostic of LPR

• Subglottic edema • Diffuse edema

• Ventricular obliteration • Granuloma

• Vocal fold edema

(48)

Outline

7.GERD and Upper Airway Disorders

8.GERD and Asthma

(49)

GERD and Asthma

•

• William Osler noted William Osler noted “…“… attacks may be due to attacks may be due to direct irritation of the bronchial mucosa or

direct irritation of the bronchial mucosa or ……

indirectly, too, by reflex influences from the indirectly, too, by reflex influences from the

stomach

stomach…”…”. . •

• Up to 80% of patients with asthma have GERD.Up to 80% of patients with asthma have GERD.

Smith LJ, Winslow C. Asthma and Surgery. In

Smith LJ, Winslow C. Asthma and Surgery. In Asthma & Rhinitis 2Asthma & Rhinitis 2. . Bussee W and Holgate S (eds). Blackwell Science 2000, pp 1834

(50)

Risk factors for exacerbation of

difficult-to-treat asthma

39 had 3 severe exacerbations/yr

136 subjects

29 had 1 severe exacerbation/yr

(51)

Conclusions

1) Odds ratio (OR) associated with 3 exacerbations a) severe sinus disease, OR 3.7

b) GERD, OR 4.9 c) URIs, OR 6.9

d) Psychological dysfunction, OR 10.8 e) Obstructive sleep apnea, OR 3.4

2) All patients with frequent exacerbations had 1/5 while 52% had 3/5

(52)

Effects of 24 weeks of lansoprazole on

asthma in patients with GERD symptoms

Multicenter, DB, randomized,

placebo-controlled trial of 206 subjects with moderate-to-severe asthma with reflux symptoms given lansoprazole, 30 mg bid vs. placebo.

(53)

Did not improve symptoms by: a) Assessment by:

1) participant 2) investigator

b) Pulmonary function studies c) Decrease in albuterol use But did:

a) Decrease asthma exacerbation

b) Improve quality of life.

Littner MR, et al: Chest 2005; 128: 1128.

(54)

Randomized DBPC Study of 770

Subjects with GERD and Asthma

• Randomized to receive esomeprazole 40 mg or P

2x QD for 16 wk

• No statistical difference in morning PEF overall

• Patients with nocturnal symptoms (NOC) improved AM PEF 8.7-L/min ( p =0.03) and PM 10.2-L/min (p=0.012) over placebo

• 304 subjects on LABA improved both AM (12.2-L/min, p= 0.017) and PM (11.1-(12.2-L/min, p =0.024) PEF, if they had GERD and NOC

• Conclusion: esomeprazole improves PEF in patients with asthma and GERD and NOC

(55)

Cochrane Data Base Review of

GERD Treatment for Asthma in Adults and

Children (2006)

• 12 randomized controlled trials of Rx for GERD in adults and children

• 2 independent reviewers

• Interventions included proton pump inhibitors (6), H₂ receptor antagonists (5), surgery and conservative management (1)

• Temporal relationship in 4 trials found between asthma and GERD

• Anti-reflux Rx did not consistently improve lung function, asthma symptoms, nocturnal asthma and medication use

• Conclusion: No overall improvement but subgroups may gain benefit

(56)

Outline

(57)

GERD and Asthma and Upper Airway Disorders

Treatment

• Empiric acid suppression – Proton pump inhibitors – H2 blockers • Lifestyle changes – Diet – Weight loss – Cigarette smoking – EtOH

– Elevation head of bed

• Modification of Rxs which aggravate GER • Increase dose of PPIs

after 6-8 weeks

• Confirmatory testing or GI consultation

(58)

(59)

(60)

(61)

Treatment Data on the Use of Proton-Pump Inhibitors and Histamine₂-Receptor Antagonists

(H₂-Blockers)*

• Healing of esophagitis

Proton-pump inhibitor

Superior to placebo (83% vs. 18%) at 8 wk; NNTB, 1.7 Superior to H₂-blocker (83% vs. 18%); relative risk, 0.51 Superior to H₂-blocker (84% vs. 52%); relative risk, 0.51 Significant Dose-response effect at 4 wk

Low dose vs. standard dose once daily: NNTB, 10 Standard dose vs. high dose once daily: NNTB, 25

* Relative risk refers to the probability of treatment failure in the active-treatment group. NNTB denotes number of patients needed to treat to benefit one patient.

(62)

Treatment Data on the Use of Proton-Pump

Inhibitors and Histamine

₂

-Receptor

Antagonists (H

₂

-Blockers)*

• Healing of esophagitis (cont’d)

H₂-blocker

Superior to placebo (41% vs. 20%) at 6 wk; NNTB, 5

No significant dose-response effect (standard dose vs. high dose twice daily)

(63)

(H₂-Blockers)*

• Resolution of heartburn†

Esophagitis

Proton-pump inhibitor superior to placeob (56% vs.8%) at 4 wk; NNTB 2 to 3

Proton-pump inhibitor superior to H₂ blocker (77% vs. 48%) at 4 to 12 wk

H₂-blocker superior to placebo (56% vs. 45%) at 12 wk

No significant dose-response effect for proton-pump inhibitor at 4 wk

Low dose vs. standard dose once daily: 75% vs. 79% Standard dose vs. high dose once daily: 73% vs. 76%

†Resolution of heartburn is generally defined as no symptoms for 7 days. Kahrilas PJ. N Engl J Med 2008;359:1700-7

(64)

(H₂-Blockers)*

• Resolution of heartburn† (cont’d)

Patients without know esophagitis

Proton-pump inhibitor superior to placebo (36.7%vs. 9.5%); NNTB, 3 to 4

Proton-pump inhibitor superior to H₂-blocker (61% vs. 40%); NNTB, 5

H₂-blocker superior to placebo (relative risk, 0.77; 95% CI, 0.60 to 0.99)

No significnat does-response effect for H₂-blocker at 8 wk% Standard dose vs. high dose twice daily: 45.8% vs.

44.8%

*Relative risk refers to the probability of treatment failure in the active-treatment group. NNTB denotes number of patients needed to treat to benefit one patient.

†Resolution of heartburn is generally defined as no symptoms for 7 days.

(65)

(H₂-Blockers)*

• Maintenance therapy‡

Remission of esophagitis

Proton-pump inhibitor superior to placebo (93% vs.29%)

Low dose of proton-pump inhibitor sufficient in 35 to 95% of patients

Remission of heartburn

Acceptable symptom control with low-dose,

intermittent therapy with proton-pump inhibitor in 83 to 92% of patients without esophagitis

*Relative risk refers to the probability of treatment failure in the active-treatment group. NNTB denotes number of patients needed to treat to benefit one patient

‡The duration of maintenance therapy was 6 to 12 months Kahrilas PJ. N Engl J Med 2008;359:1700-7

(66)

Consultation for GERD

1. Typical reflux

a. If surgery contemplated, gastroenterology consult indicated

b. If patient not responding to therapy

c. If patient has any suspected complication (stricture, carcinoma, Barrett’s

esophagus)

(67)

(68)

(69)

(70)

(71)

GERD – two main categories

• GERD with erosive esophagitis

• GERD without erosive esophagitis = NERD (non-erosive reflux disease)

(72)

Patients experiencing daily heartburn at

baseline and after 4 weeks of treatment

49%

Venables et al. Scand J Gastroenterol 1997

H₂RA PPI

Baseline After 4 weeks of treatment

P a ti e n ts ( % ) 8% 19% 0 10 20 30 40 50 60 70 80 90 100

(73)

1_{A Gallup survey on heartburn across America. 1988} 2_{Jones et al. Gut 1990}

The prevalence of GERD is widely

underestimated

• Only a minority of patients with symptoms of

GERD seek medical help1

• Patients with symptoms of GERD are often

(74)

1_{Dent et al. Gut 1998}

What is the role of lifestyle factors in

GERD?

• Contrary to commonly held opinion, lifestyle factors are not a dominant element in the

pathogenesis of erosive esophagitis1

• More research is needed to determine the role of lifestyle factors in

endoscopy-negative reflux disease1

• Lifestyle factors that may contribute to GERD include:

– smoking

– certain foods and drinks – certain medications

(75)

Dietary factors that may aggravate

GERD symptoms

• Caffeinated products • Peppermint • Fatty foods • Chocolate • Spicy foods

• Citrus fruits and juices

• Tomato-based products

(76)

Helicobacter pylori in GERD

• Infection with H pylori may cause a variety of gastric diseases

• In the context of GERD, however, there is

controversy regarding symptom improvement after therapy to

(77)

1_{Dent et al. Gut 1998}

• Now considered to be of

very limited practical value in

the diagnosis of GERD1

• May be helpful in the

detection of subtle strictures and hiatal hernias in patients with dysphagia

• May be helpful in identifying pathologies unrelated to

GERD

(78)

A. Therapy for Mild GERD

1. Mild or PRN GERD

a. Life-style changes

(79)

B. Therapy for Mild to Moderate GERD

(cont’d)

1. Histamine type-2 receptor antagonists

(H₂RAs) standard of care

d. They can be used interchangeably

e. OTC H₂RAs are particularly useful

before heavy meal or exercise or activity that potentiates reflux

f. Famotidine 10 mg taken before evening meal demonstrated to

prevent reflux and restore sleep in patients awaked by GERD(1)

(80)

B. Therapy for Mild to Moderate GERD

(cont’d)

1. Histamine type-2 receptor antagonists g. Antacids provide more rapid

response

h. The peak potency of OTC H₂RAs and

antacids are similar but H₂RAs last

(81)

Characteristics of the Proton Pump Inhibitors (PPIs) Generic

Name Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole

Trade Name (Mfr.) Nexium (AstraZeneca) Prevacid (TAP) Prilosec (AstraZeneca) Protonix

(Wyeth) Aciphex_(Eisai, Janssen) Contra-indications Hyper-sensitivity to the drug or another benzimida-zole PPI

Yes Yes Yes Yes Yes

Most common adverse events a Headache (4%) Diarrhea (4%) Abdominal pain (4%) Diarrhea (4%) Abdominal pain (2%) Headache (7%) Diarrhea (3%) Headache (6%) Diarrhea (4%) Flatulence (2%) Headache (2%)

a _{Events equal or higher than placebo}

(82)

Characteristics (contd.) Generic

Name Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole

Trade Name (Mfr.) Nexium (AstraZeneca) Prevacid (TAP) Prilosec (AstraZeneca) Protonix

(Wyeth) Aciphex_(Eisai, Janssen) Pregnancy Category B B C B B Pediatric use (minimum age for which use is indicated) 18 18 18 18 18

Metabolism Primarily via

CYP2C19 Primarily via CYP3A and CYP2C19 Primarily via CYP2C19 and CYP3A4; undergoes extensive presystemic metabolism Primarily via CYP2C1 9 and CYP3A4 Primarily via CYP3A and CYP2C19

a _{Events equal or higher than placebo}

(83)

Characteristics of the (PPIs)

Generic

(Wyeth) Aciphex_(Eisai, Janssen) Drug interactions with: Benzo-diazepines that are metabolized by oxidation (eg, diazepam, triazolam) Clearance of diazepam is reduced 45% Interaction not

likely Clearance of benzo-diazepine is Reduced

Interaction not

likely Interaction not likely

Cilostazol Not reported Not reported Plasma

concentration of cilostazol may be

increased

Not reported Not reported

Cyclosporine Not reported Not reported Concentration of cyclosporine may be

increased

Not reported Not reported

(84)

Characteristics of the PPIs

Generic

(Wyeth) Aciphex_(Eisai, Janssen) Digoxin Not reported Not reported AUC of digoxin

may be increased

Not reported AUC of digoxin is increased 19%

Itracon-azole Absorption and activity of itraconazole may be reduced Absorption and activity of itraconazole may be reduced Bioavailability of itraconazole is reduced Absorption and activity of itraconazole may be reduced Absorption and activity of itraconazole may be reduced Keto-conazole Absorption and activity of ketoconazole may be reduced Absorption and activity of ketoconazole may be reduced Absorption and activity of ketoconazole may be reduced Absorption and activity of ketoconazole may be reduced Bio-availability of ketoconazole is reduced 30%

Phenytoin Interaction not

likely Interaction not likely Clearance of phenytoin is reduced

Interaction not

likely Interaction not likely

(85)

Characteristics of the PPIs

Generic

(Wyeth) Aciphex_(Eisai, Janssen) Sucralfate Should administer at least 30 minutes before sucralfate Bioavailability of lansoprazole is reduced 17%; should administer at least 30 minutes before sucralfate Bioavailability of omeprazole is reduced 16%; should administer at least 30 minutes before sucralfate Should administer at least 30 minutes before sucralfate Should administer at least 30 minutes before sucralfate

Theo-phylline Interaction not_likely Clearance of theophylline is increased 10% Interaction not likely Interaction not likely Interaction not likely Warfarin Interaction not

likely Interaction not likely Clearance of warfarin is reduced Interaction not likely Interaction not likely

(86)

Characteristics of the (PPIs)

Generic

(Wyeth) Aciphex_(Eisai, Janssen) Adminis-tration with food Should be administered at least 1 hour before a meal Should be administered before eating Should be administered before eating May be administered without regard to food

Has not been evaluated; should be administered after the morning meal in the treatment of duodenal ulcer Recom-mended dosage adjustments precautions in special populations Do not exceed a dosage of 20 mg once a day in patients with severe hepatic impairment Dosage reduction should be considered in patients with severe hepatic impairment Dosage reduction should be considered in patients with hepatic impairment and in Asian patients Caution must be exercised in patients with severe hepatic impairment Caution must be exercised in patients with severe hepatic impairment

(87)

Characteristics of the (PPIs)

Generic

(Wyeth) Aciphex_(Eisai, Janssen) Products Delayed-release capsules containing enteric-coated pellets: 20 mg, 40 mg Delayed-release capsules containing enteric-coated granules: 15 mg, 30 mg Unit-dose packets containing enteric-coated granules for delayed-release oral suspension: 15 mg, 30 mg Delayed-release capsules containing enteric-coated granules: 10 mg, 20 mg, 40 mg Delayed-release enteric-coated tablets: 20 mg, 40 mg (following reconstitution and dilution, administered by intravenous infusion over a period of approximately 15 minutes) Delayed-release enteric-coated tablets: 20 mg

(88)

Characteristics (contd.)

Generic

(Wyeth) Aciphex_(Eisai, Janssen) Capsules or tablets should not be opened/ split, chewed, or crushed

Yesb _Yesc _Yes _Yesd _Yes

b _{Contents can be mixed with applesauce without chewing.}

c _{Contents can be sprinkled on applesauce, etc., or mixed in juice. Oral suspension used in 2 tbsp. water,}

stirred and swallowed immediately. With nasogastric tube, capsule can be mixed in 40 ml of juice.

d _{injection formulation administered IV.}

(89)

E. Promotility Therapy for GERD

1

1. Cisapride (Propulsid. Cisapride (Propulsid®®) and metoclopramide) and metoclopramide

(Reglan

(Reglan®®). Cisapride removed from market.). Cisapride removed from market.

a. These have efficacy similar to standard-dose H₂RAs

b. Metoclopramide has been associated with drowsiness, irritability,

extra-pyramidal effects (1)

(90)

E. Promotility Therapy for GERD

(cont’d)

1. Cisapride and metoclopramide

c. Cisapride provides symptomatic relief and healing of esophagitis with results comparable to

cimetidine 400 mg q.i.d. or ranitidine 150 mg b.i.d. and superior to placebo

Galmiche JP et al. Dig Dis Sci 1990;35:649-55 Lepoutre L et al. Digestion 1990;45:109-14

(91)

E.

Promotility Therapy for GERD

((contcont’’d)d)

1. Cisapride and metoclopramide 1. Cisapride and metoclopramide

d. Combined therapy (cimetidine and d. Combined therapy (cimetidine and

either metoclopramide, 10 mg

either metoclopramide, 10 mg q.i.d.q.i.d.

or cisapride, 10 mg

or cisapride, 10 mg q.i.d.q.i.d.) cause ) cause improved healing of esophagitis improved healing of esophagitis

compared with cimetidine alone compared with cimetidine alone

Lieberman DA et al. Ann Intern Med 1986;104:21

Lieberman DA et al. Ann Intern Med 1986;104:21--66 Galmiche JP et al. Gut 1988;29:675

(92)

E. Promotility Therapy for GERD

(cont’d)

e. Cisapride may be an effective maintenance therapy for GERD

Toussaint J et al. Gut 1991;32:1280-5

(93)

(cont’d)

f. Combination of cisapride and

ranitidine superior to ranitidine alone but inferior to omeprazole alone

(94)

(cont’d)

g. Fatal dysrhythmias associated with the combination of

cisapride and medications metabolized by cytochrome P-450 (antifungal agents and some antimicrobials)

Chan

Chan--Tompkins NH et al. Clin Infect Dis 1997;24:1285Tompkins NH et al. Clin Infect Dis 1997;24:1285 Rampe D et al. FEBS Lett 1997;417:28

(95)

E. Promotility Therapy for GERD

(cont’d)

h. PPIs provide greater control of acid reflux with minimal risk and no

(96)

A.

Therapy for Mild GERD

(con’t)

1. Mild or PRN GERD

b. Antacids and over-the-counter acid suppressants

Comment: Alginic acid more effective than placebo (Gaviscon®)

Graham DY et al. Dig Dis Sci 1983;28:559-63 Buts JP et al. Eur J Pediatr 1987;146:156-8

(97)

A.

Therapy for Mild GERD

(cont’d)

1. Mild or PRN GERD

c. Combined antacid/alginic acid therapy may be superior to

antacids alone

Castell DO et al. Dig Dis Sci 1992;37:589-93 Stanciu C et al. Lancet 1974;1:109-11

(98)

A.

Therapy for Mild GERD

(cont(cont’’d)d)

1. Mild or PRN GERD 1. Mild or PRN GERD

d. Efficacy proven in approximately d. Efficacy proven in approximately

20% of patients using these OTC 20% of patients using these OTC agents

agents

Lieberman DA. Arch Intern Med 1987;147:717-20 Behar J. N Engl J Med 1975;293:263-8

(99)

Gauchos and Cowboys

• Courage is being scared to death – but saddling up anyway.

• El coraje tiene miedo a morir, pero sigamos cabalgando

-- John Wayne

(100)

• Asthma Clinic Research Center – network of

academic asthma research centers – constituted and funded by the American Lung Association

(ALA)

• Purpose: conduct clinical trials in asthma

(101)

Acid Reflux in Children with Asthma

• Hypothesis: children (6-17 yo) with symptomatic asthma have improved asthma control with medical treatment of esophageal reflux using proton-pump inhibitor (PPI),

lansoprazole, compared to placebo- treated children. • General Goal: enroll children with poor asthma control

whom asthma physicians might consider evaluating for GERD or treatment with a PPI

• Eligible children may be identified by: screening at participating centers, existing patient registries,

advertisements, or referrals.

• USF Division Allergy/Immunology: 4 enrolled patients – 2 have randomized to study medication. Recruitment until 2011.

(102)

(103)

Lockey et al. Gastroenterology 1997 Age (years) 25 - 34 35 - 44 45 - 54 55 - 64 65 - 74 0 20 40 60 80 Any episode of GERD symptoms At least weekly episodes of GERD symptoms Males Females P re v a le n c e ( % )

GERD is a common and significant

problem

(104)

Multi-Center DBPC of 207 Patients with GERD

Symptoms and Moderate to Severe Asthma

• Lansoprazole 30 mg BID or placebo BID for 24 weeks • Asthma symptoms, albuterol use, PEF, FEV1, FVC,

and investigator-assessed asthma Sx at 24 wks did not improve

• The asthma quality-of-life with standardized activities improved (p=0.025)

• Exacerbations (p=0.17) and oral corticosteroid-treated exacerbations (p=0.016) improved

• Conclusions: In adult patients with moderate to

severe asthma, lansoprazole BID reduced asthma exacerbations and improved QOL, particularly in patients receiving more than one asthma-control medication

(105)

C. Therapy for Moderate to Severe GERD (cont’d)

1. H₂RAs in divided doses are effective

treatment in many patients with less severe GERD.

e. H₂RAs at these doses still inferior to proton pump inhibitors (PPI) and

more costly at high doses

Behar J et al. Gastroenterology 1978;74:441-8

Sontag S et al. Arch Intern Med 1987;147:1485-91 Euler Ar et al. Am J Gastroenterol 1993;88:520-4

(106)

D. Proton Pump Inhibitors (PPIs)

(cont’d)

2. Concerns about PPIs

a. PPIs decrease gastric acid secretion (1) b. This leads to increased gastrin

production from antral-G cells and

increased serum gastrin levels (2 to 4 times basal) (2)

c. Question whether or not these changes in serum gastrin may produce

dangerous trophic effects on gastric mucosa

(1) Klinkenburg-Kriol EC et al. Gastroenterology 1990;99:621-8 (2) Jansen JB. Gastroenterology 1990;99:621-8

(107)

D. Proton Pump Inhibitors (PPIs)

(cont’d)

2. Concerns about PPIs

d. Omeprazole and lanzoprazole are approved for 1 yr of continuous usage

e. No cases of gastric carcinoid tumor in patients receiving PPIs

f. Atrophic gastritis not reported with long-term omeprazole

(108)

D. Proton Pump Inhibitors (PPIs) (cont’d)

2. Concerns about PPIs 2. Concerns about PPIs

g. Cobalamin absorption may be g. Cobalamin absorption may be

decreased with chronic PPI but no decreased with chronic PPI but no

change in serum levels reported change in serum levels reported

after 7 yr of therapy (1) after 7 yr of therapy (1)

h. No evidence of bacterial h. No evidence of bacterial

overgrowth after long

overgrowth after long--term acid term acid suppression (2)

suppression (2)

i. Potential benefit of chronic PPI i. Potential benefit of chronic PPI

therapy outweighs risk in patients therapy outweighs risk in patients with chronic or complicated GERD with chronic or complicated GERD (1) Schenk BE et al. Aliment Pharmacol Therap 1996;10:541

(1) Schenk BE et al. Aliment Pharmacol Therap 1996;10:541--55 (2) Hutchinson S et al. Age Ageing 1997;26:87

(109)

• Esophagitis occurs when excessive reflux of acid and pepsin results in necrosis of surface layers of

esophageal mucosa, causing erosions and ulcers. Impaired clearance of the refluxed gastric juice from the esophagus also contributes to damage in many patients. Whereas some gastroesophageal reflux is normal (and relates to the ability to belch), several factors may predispose patients to pathologic reflux, including hiatus hernia, lower esophageal sphincter hypotension, loss of esophageal peristaltic function,

abdominal obesity, increased compliance of the hiatal canal, gastric hypersecretory states, delayed gastric emptying, and overeating. Often multiple risk fadtors are present.

(110)

(111)

Richter. Am J Gastroenterol 2000 Misc Misc Asthma Asthma ENT ENT Chest pain Chest pain Non

Non--erosive reflux diseaseerosive reflux disease

Erosive esophagitis Erosive esophagitis Yes No Need to investigate role of acid 0% 100% Prevalence of GERD

The pyramid of diseases associated

with GERD

(112)

Shaw et al. Am J Gastroenterol 2001

Reflux disease questionnaire

• The patient grades the frequency and severity over the previous 4 weeks of

– a burning feeling behind the breastbone – pain behind the breastbone

– an acid taste in the mouth

– unpleasant movement of material upwards from the stomach

(113)

DeVault et al. Am J Gastroenterol 1999

When is history not enough?

• Additional diagnostic procedures are indicated if

– the history is atypical and the diagnosis of GERD

is uncertain

– alarm symptoms are present

– symptoms are frequent and long-standing – symptoms do not respond to therapy

(114)

Alarm symptoms suggesting early

work-up

• Dysphagia • Bleeding

• Weight loss

• Choking, chronic cough, shortness of breath, or hoarseness

(115)

• Allows direct visualization of the esophageal

mucosa and biopsy if necessary

• The technique of choice for determining the

presence and severity of erosive esophagitis

• The only reliable method for the detection of

Barrett’s esophagus

(116)

• Allows investigation of

– the amount and timing of reflux

– the correlation between reflux and symptoms

– the effect of therapy on reflux

• In general, most useful in

– endoscopy-negative patients – patients with chest pain or

pulmonary/upper respiratory symptoms

– patients with refractory symptoms1

1_{DeVault et al. Am J Gastroenterol 1999}

(117)

Treatment of GERD

A. Therapy for Mild GERD

C. Therapy for Moderate to Severe GERD D. Proton Pump Inhibitors (PPIs)

F. Maintenance Therapy for GERD G. Surgical Therapy for GERD

H. Consultation for GERD

I. Barrett’s Esophagus

(118)

B. Therapy for Mild to Moderate GERD

1. Histamine type

1. Histamine type--2 receptor antagonists 2 receptor antagonists (H

(H₂₂RAs) standard of careRAs) standard of care

a. Four H

a. Four H₂₂RAs available by prescriptionRAs available by prescription 1) Ranitidine (Zantac 1) Ranitidine (Zantac®®), 150 or 300 mg), 150 or 300 mg 2) Ninatizine (Axid 2) Ninatizine (Axid®®), 150 or 300 mg), 150 or 300 mg 3) Famotidine (Pepsid AC 3) Famotidine (Pepsid AC®®), 10 mg), 10 mg 4) Cimetidine (Tagamet 4) Cimetidine (Tagamet®®), 300, 400 mg), 300, 400 mg b. The doses OTC usually one

b. The doses OTC usually one--half of half of standard lowest prescription dose

standard lowest prescription dose

c. Doses shown to decrease gastric acid,

particularly post

(119)

Treatment of GERD

(120)

Treatment of GERD

C. Therapy for Moderate to Severe GERD

D. Proton Pump Inhibitors (PPIs) E. Promotility Therapy for GERD

(121)

C. Therapy for Moderate to Severe GERD

1. H

1. H₂₂RAs in divided doses are effective RAs in divided doses are effective treatment in many patients with less

treatment in many patients with less

severe GERD.

a. 33 Randomized trials with more . 33 Randomized trials with more than 3,000 patients

than 3,000 patients

b. Symptomatic relief expected of 27%

of placebo

of placebo--treated and 60% of treated and 60% of H

H₂₂RARA--treatedtreated

c. Esophagitis healed in 24% of

placebo

placebo-- treated and 50% of Htreated and 50% of H₂₂RARA- -treated

treated

d. Higher doses and more frequent

d. Higher doses and more frequent dosing dosing of of H

(122)

Treatment of GERD

A.

A. Therapy for Mild GERDTherapy for Mild GERD B.

B. Therapy for Mild to Moderate GERDTherapy for Mild to Moderate GERD C.

C. Therapy for Moderate to Severe GERDTherapy for Moderate to Severe GERD D.

D. Proton Pump Inhibitors (PPIs)Proton Pump Inhibitors (PPIs) E.

E. Promotility Therapy for GERDPromotility Therapy for GERD F.

F. Maintenance Therapy for GERDMaintenance Therapy for GERD G.

G. Surgical Therapy for GERDSurgical Therapy for GERD H.

H. Consultation for GERDConsultation for GERD I.

I. BarrettBarrett’’s Esophaguss Esophagus J.

(123)

D. Proton Pump Inhibitors (PPIs)

1. Symptomatic relief and esophagitis healed

better with PPIs than H

better with PPIs than H₂₂RAsRAs

a. Symptomatic relief in 27% of placebo

a. Symptomatic relief in 27% of placebo- -treated, 60% of H

treated, 60% of H₂₂RARA--treated, and 83% treated, and 83% of PPI

of PPI--treated patientstreated patients

b. Esophagitis healed in 24% of placebo

b. Esophagitis healed in 24% of placebo- -treated, 50% of H

treated, 50% of H₂₂RARA--treated and 78% treated and 78% of PPI

of PPI--treatedtreated

c. PPIs eliminate and heal esophagitis

more frequently and rapidly than other agents

d. Higher doses and more frequent doses of

H

H₂₂RAs are more effective but inferior RAs are more effective but inferior and more costly than PPIs

(124)

Treatment of GERD

(125)

(126)

Treatment of GERD

F. Maintenance Therapy for GERD

G. Surgical Therapy for GERD H. Consultation for GERD

(127)

F. Maintenance Therapy for GERD

1. GERD is a chronic condition and

continuous therapy indicated to prevent complications of GERD (esophagitis,

stricture, adenocarcinoma, etc.)

a. Effective maintenance should control symptoms and prevent complications b. Adjustments in medications are

necessary

(128)

(cont’d)

c. Full dose of H₂RA given once daily

not effective therapy for GERD

d. Reduced doses of PPIs have not been shown consistently to be effective for long-term therapy

Bank et al. Gastroenterology 1991;100:A29 Dent J et al. Gut 1994;35:590-8

(129)

F. Maintenance Therapy for GERD

(cont’d)

e. PPIs but not H₂RAs prevent recurrent

strictures

Marks RD et al. Gastroenterology 1994;106:907-15 Gough et al. Aliment Pharmacol Ther 1996;10:529-39

(130)

Treatment of GERD

G. Surgical Therapy for GERD

(131)

G. Surgical Therapy for GERD

1. Antireflux surgery, performed by an

experienced surgeon, is a maintenance option for patients with documented

GERD.

a. Two published studies show surgery more effective than medical therapy. (One study compared antacids and lifestyle changes over 36-months.

Second study compared surgery versus ranitidine and metoclopramide.)

DeMeester TR et al. Ann Surg 1986;204:9-20 Spechler SJ. N Eng J Med 1992;326:786-92

(132)

G. Surgical Therapy for GERD

(cont’d)

GERD.

b. Randomized trial 310 patients

initially controlled with omeprazole 40 mg per day found surgery to be slightly superior (maintenance of esophagitis healing and symptoms) to omeprazole 20 mg per day at the end of 3 yr period.

(133)

G. Surgical Therapy for GERD

(cont’d)

GERD.

c. If dose is titrated to 40-60 mg per day of omeprazole medical and surgical treatments equal.

(134)

Treatment of GERD

(135)

Treatment of GERD

(136)

I. Barrett’s Esophagus

Gastroenterology consult

(137)

Treatment of GERD

(138)

J. Refractory to Therapy

1. Refractory to medical therapy is rare.

The diagnosis should be confirmed

before high dose acid suppression or

antireflux surgery.

a. This may involve pH study, endoscopic

studies, manometric studies. Recent

report of 2 patients who had refractory

reflux (by pH study and symptoms)

while taking omeprazole, who had better

acid suppression with high

acid suppression with high--dose Hdose H₂₂- -receptor therapy.

receptor therapy.

Leite LP et al. Am J Gastroenterol 195;90:1874

(139)

J. Refractory to Therapy (cont’d)

1. Refractory to medical therapy is rare. The diagnosis should be confirmed before high dose acid suppression or antireflux surgery.

b. Cases rare but emphasize need for individualizing therapy.

(140)

(141)

(142)

Symptom Reference Population Size Definition of extra-oesophageal symptom Prevalence of extra-oesophageal symptom in children with GERD Asthma 13.2% vs. 6.8% of controls (P < 0.0001) Respiratory symptoms Pneumonia El-Serag et al. 1980 with GERD + 7980 controls Physician diagnosis 6.3% vs. 2.3% of controls (P < 0.0001) Bronchiectasis 1% vs. 0.1% of controls (P < 0.0001)

Prevalence of Extra-Oesophageal Symptoms in Children with GERD

ALTE, apparent life-threatening event; ENT, ear, nose and throat; GERD, gastro-oesophageal

reflux disease; RI, reflux index (% of total time when pH < 4); WHO, World Health Organization

(143)

Symptom Reference Population Size Definition of extra-oesophageal symptom Prevalence of extra-oesophageal symptom in children with GERD ALTE Tolia 173 with GERD + Physician 20% vs. 31% of controls (P < 0.12) Respiratory symptoms General respiratory symptoms

et al. 169 controls diagnosis 49% vs. 63% of controls (P < 0.01)

General respiratory symptoms

Khalaf et al. 42 with

severe RI + 66 controls Respiratory distress syndrome defined by clinical features and positive chest radiograph 62% vs. 36% of controls (P = 0.02)

(144)

Symptom Reference Population Size Definition of extra-oesophageal symptom Prevalence of extra-oesophageal symptom in children with GERD Sinusitis El-Serag 1980 with GERD + Physician 4.2% vs. 1.4% of controls (P < 0.0001) ENT symptoms

Otitis media et al. 7980 controls diagnosis 2.1% vs. 4.6% of controls (P < 0.0001) Dental erosion

Linnett et al. 52 with

GERD + 52 healthy

controls

WHO criteria for caries

14% had

erosion vs. 10% of controls (P < 0.05)

(145)

Symptom Reference Population Size Definition of extra-oesophageal symptom Prevalence of extra-oesophageal symptom in children with GERD Dental symptoms Dental erosion

Ersin et al. 38 with

GERD + 42 healthy

controls

WHO criteria for caries Eccles & Jenkins index for erosion by GERD 76% had erosion vs. 10% of controls (P < 0.0001) 37% had severe erosion vs. 1% of controls (P < 0.05)

(146)

(147)

Tolia V, Vandenplas Y.. Aliment Pharmacol Ther 2009;29(3):258–272 continued

(148)

Symptom Reference Population size Diagnosis of reflux symptom Prevalence of GERD in patients with extra-oesophageal symptoms Respiratory symptoms Asthma Stordal et al. 872 asthmatics + 264 controls GERD questionnaire 19.7% of asthmatics had a positive GERD symptom score vs. 8.5% of controls (odds ratio, 2.6, P < 0.001)

Prevalance of GERD in Children with Extra-Oesophageal Symptoms

ALTE, apparent life-threatening event; ATS, American Thoracic Society; ENT, ear, nose and throat, GERD, gastro-oesophageal reflux disease; GI, gastrointestinal; GINA, Global Initiative for Asthma; ISAAC,

International Study of Asthma and Allergies in Childhood; NIH, National Institutes of Health; RI, reflux index

Tolia V, Vandenplas Y.. Aliment Pharmacol Ther 2009;29(3):258–272

(149)

Symptom Reference Population size Diagnosis of reflux symptom Prevalence of GERD in patients with extra-oesophageal symptoms Respiratory symptoms

Asthma Barakat et al. 75 asthmatics + 25 controls Endoscopy / ultrasound GI symptoms in 65% of those with asthma vs. 16% of controls (P < 0.001)

(150)

Symptom Reference Population size Diagnosis of reflux symptom Prevalence of GERD in patients with extra-oesophageal symptoms Respiratory symptoms

Asthma Chopra et al. 80 asthmatics + 10 controls

Presence of

sciatica tracer in oesophagus in more than two frames 39% of asthmatics demonstrated reflux on scintiscanning vs. 0% of controls (P < 0.05)

(151)

Symptom Reference Population size

Diagnosis of reflux symptom

Prevalence of GERD in patients with extra-oesophageal

symptoms

Respiratory symptoms

Asthma Hughes et al. 9 asthmatics + 7 controls Oesophageal pH monitoring; reflux defined as a decrease in pH to < 4 for at least 15 s Gastro-oesophageal reflux occurred in 33% of asthmatics vs. 57% of controls. No significant difference between the two groups in number or duration of reflux episodes or % of time pH < 4

(152)

Symptom Reference Population size

Diagnosis of reflux symptom

Prevalence of GERD in patients with extra-oesophageal

symptoms

Respiratory symptoms

Asthma Debley et al. 296 asthmatics

+ 1510 controls Positivie response to selected questionnaire questions 19.3% of adolescents with current asthma had GERD symptoms vs. 2.5% of adolescents without asthma (P < 0.001)

(153)

Symptom Reference Population size Prevalence of GERD in patients with extra-oesophageal symptoms ENT symptoms Laryngotracheitis Contencin and Narcy 8 patients consulting for laryngotracheitis + 6 controls Dual-channel pH monitoring. Pathological gastro-oesophageal reflux defined as RI > 5.2% 62.5% of patients had pathological gastro-oesophageal reflux vs. 16.6% of controls

(154)

(155)

Reference Pop. size Study design Definition of extra-oesophageal symptom

Drug and dosage Outcome

Khoshoo and Haydel 44 Investigator-blinded prospective trial Asthma _≥ 3

episodes per year despite optimal treatment Group A: esomeprazole (40 mg/day) / metoclopramide, Group B: ranitidine (150 mg 3 times daily), Group C: control (fundoplication). All had previously had PPI / prokinetic for 1 year Following 6 months treatment, group B had significantly more exacerbations than groups A and C

Outcomes of GERD Drug Therapy on Extra-Oesophageal Symptoms

(156)

Reference Pop. size

Study design Definition of

extra-oesophageal symptom Drug and dosage Outcome Stordal et al. 38 with asthma Randomized placebo-controlled trial Physician-diagnosed asthma Omeprazole 20 mg once daily or placebo for 12 weeks Asthma symptoms scored by two questionnaires did not differ significantly

between groups following

treatment Outcomes of GERD Drug Therapy on

Extra-Oesophageal Symptoms